Metastatic renal cell carcinoma (RCC) is a dismal disease, with nearly uniform resistance to radiotherapy, chemotherapy and immunotherapy. Recently, the availability of molecularly-targeted therapy against vascular endothelial growth factor (VEGF) has dramatically altered the therapeutic landscape of RCC. One such approach involves the VEGF-binding antibody, bevacizumab. The CALGB has completed an Intergroup Phase III trial of interferon alpha (IFNA) plus bevacizumab versus IFNA alone in 732 patients with metastatic renal cell carcinoma (CALGB 90206), representing one of the largest phase III trials conducted to date in RCC. Baseline paraffin-embedded tissue was collected on 591 of these patients in addition to plasma and urine samples obtained at baseline and after 6 weeks of therapy. This is a unique opportunity for analysis of this tissue to provide insight into the biology of RCC, the mechanisms of response to bevacizumab-based therapy, and to develop a new predictive model for response using extensive biomarker analyses. Our central hypothesis is that genomic alterations and expression changes in genes involved in angiogenesis and other receptor kinase pathways are predictive of outcome in patients with renal cell carcinoma treated with interferon 1 bevacizumab. We will test whether overall survival is associated with: 1) von Hippel Lindau gene mutation and methylation, 2) patterns of genomic alterations by array-CGH, 3) expression of protein targets using a new method of automated quantitative analysis of tissue microarrays (AQUA), and 4) plasma and urine biomarker levels at baseline and 6 weeks into therapy. We will then develop a new predictive multivariate model for risk stratification of patients with metastatic renal cell carcinoma, using clinical, pathologic, and molecular markers. PUBLIC HEALTH RELEVANCE: Identification of molecular alterations associated with outcome after bevacizumab- based therapy will have broad implications for treatment of RCC and other cancers. This agent and the anti-angiogenic approach in general are now widely recognized as an effective treatment modality in a number of tumor types. Insight into the molecular basis for baseline response to bevacizumab will provide a knowledge base upon which to rationally select patients for such therapies in the future. The NCI Progress Review Group for Kidney and Bladder Cancer (2001) identified 13 priorities as research goals. The first two priorities were 1) Understand the biological mechanism underlying the risk factors for kidney and bladder cancer phenotypes, and 2) Identify global genetic, epigenetic, RNA expression, and proteomic alterations in tumors and place them in specific biological pathways that are essential to development, progression, response to therapy, and maintenance of subtypes of bladder and kidney cancers;This proposal directly addresses these two top priorities.